Histopathologic and proteogenomic heterogeneity reveals features of clear cell renal cell carcinoma aggressiveness
Authors: Yize Li, Tung-Shing M. Lih, Saravana M. Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J. Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J. Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A. Wyczalkowski, Michael C. Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A. Reimers, Russell Pachynski, Alexander J. Lazar, Arul M. Chinnaiyan, Brian A. Van Tine, Bing Zhang, Karin D. Rodland, Gad Getz, D.R. Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W. Marston Linehan, David Fenyö, Scott D. Jewell, Gilbert S. Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I. Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W. Chan, Christopher J. Ricketts, Alexey I. Nesvizhskii, Hui Zhang, Li Ding, Alicia Francis, Amanda G. Paulovich, Andrzej Antczak, Anthony Green, Antonio Colaprico, Ari Hakimi, Barb Pruetz, Barbara Hindenach, Birendra Kumar Yadav, Boris Reva, Brenda Fevrier-Sullivan, Brian J. Druker, Cezary Szczylik, Charles A. Goldthwaite, Chet Birger, Corbin D. Jones, Daniel C. Rohrer, Darlene Tansil, David Chesla, David Heiman, Elizabeth Duffy, Eri E. Schadt, Francesca Petralia, Gabriel Bromiński, Gabriela M. Quiroga-Garza, George D. Wilson, Ginny Xiaohe Li, Grace Zhao, Yi Hsiao, James Hsieh, Jan Lubiński, Jasmin Bavarva, Jasmine Huang, Jason Hafron, Jennifer Eschbacher, Jennifer Hon, Jesse Francis, John Freymann, Josh Vo, Joshua Wang, Justin Kirby, Kakhaber Zaalishvili, Karen A. Ketchum, Katherine A. Hoadley, Ki Sung Um, Liqun Qi, Marcin J. Domagalski, Matt Tobin, Maureen Dyer, Meenakshi Anurag, Melissa Borucki, Michael A. Gillette, Michael J. Birrer, Michael M. Ittmann, Michael H. Roehrl, Michael Schnaubelt, Michael Smith, Mina Fam, Nancy Roche, Negin Vatanian, Nicollette Maunganidze, Olga Potapova, Oxana V. Paklina, Pamela VanderKolk, Patricia Castro, Paweł Kurzawa, Pushpa Hariharan, Qin Li, Qing Kay Li, Rajiv Dhir, Ratna R. Thangudu, Rebecca Montgomery, Richard D. Smith, Sailaja Mareedu, Samuel H. Payne, Sandra Cerda, Sandra Cottingham, Sarah Haynes, Shankha Satpathy, Shannon Richey, Shilpi Singh, Shirley X. Tsang, Shuang Cai, Song Cao, Stacey Gabriel, Steven A. Carr, Tao Liu, Thomas Bauer, Toan Le, Xi S. Chen, Xu Zhang, Yvonne Shutack, Zhen Zhang
Journal: Cancer Cell (2022)

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 expression displays prognostic value. Single-nuclei RNA sequencing of the adverse sarcomatoid and rhabdoid phenotypes uncover gene signatures and potential insights into tumor evolution. In vitro cell line studies confirm the potential of inhibiting identified phosphoproteome targets. This study molecularly stratifies aggressive histopathologic subtypes that may inform more effective treatment strategies.